Adipose tissue surrounding the great vessels [perivascular (PV) adipose tissue, or PVAT] expands during obesity, is highly inflamed and correlates with coronary plaque burden and increased cardiovascular (CV) risk. A consensus is emerging that PVAT is a cause of CV disease, but direct proof is lacking. Demonstrating a pathogenic role for PVAT challenges the current paradigm that CV disease originates primarily at the intima and provides a new target for assessment and treatment of CV disease. Our laboratory has developed a robust model of PVAT transplantation to the mouse carotid artery to determine its role in eliciting vascular pathology and the mechanisms whereby PVAT interacts with metabolic factors, chemokines, inflammatory cells and the blood vessel wall. PVAT transplantation in the setting of high fat diet dramatically enhanced wire injury- induced neointimal formation and atherosclerosis, and increased adventitial inflammation and angiogenesis, providing direct evidence that PVAT plays a pathogenic role in CVD. Moreover, preliminary data suggest that transplanting PVAT from mice lacking the chemokine MCP-1 attenuates neointimal formation, consistent with pleiotropic effects of MCP-1 to promote vascular remodeling. In addition, angiotensin II (AngII) is upregulated in adipose tissue during high fat feeding and promotes adventitial remodeling and inflammation. Our central hypothesis is that PVAT synergizes with high-fat diet and AngII to enhance arterial remodeling and atherosclerosis, in part through secretion of MCP-1. To test this hypothesis, we propose three specific aims. Aim 1 will test the hypothesis that high-fat diet and AngII synergize with PVAT to enhance arterial remodeling and atherosclerosis, using PVAT from wild-type mice or AngII receptor type-1a (AT1a) knockout mice. Aim 2 will test the hypothesis that stromal-derived factor 1 (SDF-1), which increases in the intima and media soon after wire injury, is requisite for inside-out molecular crosstalk leading to enhanced arterial remodeling by PVAT. Aim 3 will test the hypothesis that MCP-1 secretion by PVAT is requisite for outside-in molecular crosstalk leading to enhanced arterial remodeling and atherosclerosis by PVAT. Using PVAT from wild-type or MCP-1 knockout mice, we will investigate an interactive role of AngII with MCP-1 in these experiments. The proposed studies are expected to provide direct evidence of a pathogenic role of PVAT in CVD, to define interactions between PVAT, high-fat diet and AngII, and to address putative molecular mechanisms of crosstalk between the blood vessel wall and PVAT. PUBLIC HEALTH RELEVANCE: The purpose of this study is to determine the role of fat that surround blood vessels also known as perivascular adipose tissue, or PVAT) in causing vascular disease. We provide evidence that the inside of the blood vessel (intima) communicates with the PVAT when the artery is injured, leading to increased obstruction of the blood vessel. We plan to determine what mediates this communication system and how it is perturbed in the setting of high fat diet.